Tuesday, September 28, 2010

An Encapsulated Human Islet Transplant Cure in Phase-IFor the last many years, I have thought that LCT was the only company actively doing clinical trials on an encapsulated islet cell cure for type-1 diabetes. However, I recently found this clinical trial record:http://www.clinicaltrials.gov/ct2/show/NCT00790257

These guys are testing human encapsulated islet cells (so not pig cells, as LCT is using). They started in November 2008 and ending in December 2013, and includes 15 people. They're doing this one trial in two phases, the first phase is only open to people who have already had an organ transplant (which I'm sure is delaying the study, since it takes a long time to recruit people like that). They call their device a "Monolayer Cellular Device", and the work is being done in Belgium

News on Otelixizumab by Tolerx

I have two tidbits on Tolerx's Otelixizumab. The first is from news article which was discussing the start of their DEFEND-2 clinical trial, which is a confirmatory phase-III trial. So that is the last stage before FDA approval. So, as the quote shows below, Tolerx is starting to look to eventual approval:

If the trial [DEFEND-2] is successful, the company plans to send the drug candidate to the U.S. Food and Drug Administration in 2012.

Obviously that is good news. For comparison, Diamyd was talking about starting the approval process in 2011, and LCT at one time was 2011, but more recently was 2013. To the best of my knowledge we have never started the marketing approval process for a non-insulin drug to target type-1 diabetes. So having three possible starts in the next 3 years is great. Although that is tempered by the fact that only one of these treatments has been tested on established diabetics, and none of them represents a cure so far.

The other piece of news is a little more technical. Here is the key quote:

The new research findings support existing data suggesting that otelixizumab may work in patients with new-onset type 1 diabetes by blocking the function of T killer/effector cells that mistakenly attack and destroy insulin-producing beta cells, while simultaneously stimulating T regulatory cells that are thought to protect against future T killer/effector destruction. Clinical data from the recently completed DEFEND-1 Phase 3 study and the ongoing DEFEND-2 confirmatory Phase 3 study will be evaluated in light of these new findings to determine whether this dual effect of otelixizumab is consistent with results from patients who have received otelixizumab.

What this means is that they believe that their experiments show that Otelixizumab works in two different ways. First, it blocks the bad killer T-cells. The cells that are directly attacking the pancreas. Second it increases the actions of the regulatory T-cells, which are cells designed to control killer T-cells. That is potentially a powerful combination (although it will be interesting to see how long it lasts). Another interesting piece of data is how selective is it? Attacking the bad killer T cells is one thing, but it would be even better to NOT attack the good killer T cells. The press release implies that it is selective, (which would be great) but this is a case where we need to see the numbers, to see exactly how selective it is.

Both Tolerx (Otelixizumab) and MacroGenics (Teplizumab) Start Separate Subcutaneous Trials
Both Tolerx and MacroGenics are starting clinical trials designed to test their respective drugs when given subcutaniously. The current clinical trials for both drugs require an IV (drip into a blood vein). Those can not be done at home. However, these studies are checking to see if the respective drugs can be injected just under the skin (called Subcutaneously, or SubQ). That is how insulin is injected. So if these clinical trials are successful, that means people would be able to inject themselves at home, rather than go to a clinic and have a nurse do it.

These are both phase-I studies and both are still recruiting new patients.
The Teplizumab study has 71 people, and should complete in July 2012, and is honeymoon only. You must be within 1 year of diagnosis.
The Otelixizumab study has 28 people, and should complete was supposed to finish in July 2010. This study is not limited to honeymoon diabetics, but you must have A1C numbers above 9%, you must generate a little C-peptide. If the study shows that the drug has the same (or similar) effect when injected like just under the skin as they see with IV drips, then I would love to see how it effects long established diabetics.

Testing C-Peptides: Fasting as good as Stimulated?A little background: When your body makes insulin, it also makes a small molecule called C-Peptide. This is very important to diabetes research, because if a researcher sees insulin in a person's blood, there is no way to know if that insulin came from an injection or from internal production. However, C-peptide only comes from internal insulin production. So when someone measures if a drug helps insulin production, what they really do is measure C-peptide. Years ago the US FDA adopted this standard, so that in order to get a new drug approved to help a diabetic produce more insulin, the drug company must show evidence that the new drug increases C-peptide levels. (Paradoxically, measuring insulin is considered a second rate way to testing insulin production, because the type-1 diabetic might have injected more insulin for any number of reasons.) C-peptide is the gold standard of measuring insulin production.

But there are two ways to measure C-peptide: fasting and after a meal (which is sometimes called a "challenge" or "stimulated"). The fasting one is quicker and easier to do (at least for the researchers, the patient may prefer a meal :-) ) But the meal one is considered a better measure of effectiveness. Basically, a fasting C-peptide measure tells you how well your body creates "basil" (ie. no food) insulin. While the meal test tells you how well your body creates "bolus" insulin (in response to food). The meal one is considered better, but the fasting one is easier.

The summary of this poster session is that the results of the two different tests are linked. So that doing a fasting test predicts what will happen for a meal test, and doing a meal test predicts what will happen for a fasting test. If confirmed by other trials, this will make it cheaper and easier to do clinical trials in the future (especially for large numbers of people) since you will only need to do a fasting test.

Press release: http://www.sys-con.com/node/1544442

Novocell Terminates Encapsulated Islet Transplant Clinical TrialYears ago, Novocell was developing an encapsulated islet cell transplant cure, similar to LCT, although my memory was that they were using human islet cells, not pig cells. In any case, the research did not move forward. They started a phase-I clinical trial in 2005, but in 2006 they stopped recruiting for it. I think that it has been moribund ever since, but they just (April 2010) officially terminated it.

The company recently changed it's name to ViaCyte, and is working on an encapsulated islet cure called "Pro-Islet". They are doing animal ("pre-clinical") studies, so I'm not following it as yet.

Final End of TT-223
A few days ago, Transition Therapeutics announced the end of clinical research for TT-223:

Transition Therapeutics announced today [17 Sept 2010] that a clinical study of gastrin analogue TT-223 in combination with a Lilly proprietary GLP-1 analogue in patients with type 2 diabetes did not meet its efficacy endpoints. Given these findings, there will be no further development of TT-223.

Press release: http://www.transitiontherapeutics.com/media/news.php

My translation: Even when we mixed it with another drug, it still did not work well enough to move forward.

So that's about as dead as you can get. (Although INGAP went through this same process and was later "reborn" by the original developers who thought it had a future even though their big pharma backers did not. Those guys are still doing clinical trials of INGAP (renamed Exsulin) and who knows what will happen?)

A little history:
TT-223 was one of the possible cures in existence when I started tracking them on my original web status page. They were initially funded by JDRF, but then Eli Lily took over development from Transition Therapeutics, the small company that JDRF had funded. JDRF got it's money back at this point because their funding was no longer needed, and they then reinvested it in something else. But Eli only continued the type-2 testing, not the type-1 testing. So almost exactly a year ago I blogged about this, and said that TT-223 was dead as far as a cure for type-1 (at least until someone started testing it again in type-1 diabetics). You can read that post here:
http://cureresearch4type1diabetes.blogspot.com/2009/09/two-possible-cures-go-to-boneyard.html
At that point I stopped following TT-223. However, an alert reader continued to follow them, and so when they issued the press release above, that reader forwarded it to me. Thanks! You know who you are.

Rituximab in the Real World
I have previously blogged on Rituximab (sold as Rituxan):
http://cureresearch4type1diabetes.blogspot.com/search/label/Rituximab
This drug is already approved for use in the US for certain diseases, and there was a recently published article on it's safety as applied to rheumatoid arthritis, which is an autoimmune disease of the same general family as type-1 diabetes. You can read that here:

This study was based on a registry of over a thousand French citizens who were treated with Rituximab and who were followed up for at least a year. So this is a much bigger study than the Phase-I study for type-1 diabetics, which was less than 90 people for 1 year.

There were two interesting results, from my point of view:

First, the overall rate of serious infection was about the same in this trial as it had been in the trials that were used to get approval for the drug in the first place. That's good news, because those approval trials generally exclude patients who have "co-morbidities" (that is: something else wrong with them). On the other hand, real world use include patients who have several different diseases. (Especially rheumatoid arthritis.) And having more than one disease raises the chance of serious infection, and that is exactly what this study was looking at. So it is good news that the side effects were no worse for real world use as for experimental use.

Second, the serious infection rate was much higher (about 5 times as high) for people who had "low IgG levels". So the authors of the study suggest that people getting Rituximab get tested for that before each dosing. Other co-morbidities that were associated with a higher chance of serious infection included chronic lung disease and/or cardiac insufficiency and extraarticular involvement. (Which are not common in type-1 diabetics, and especially not young ones.)

I think this is good safety news for this drug. Both because it shows it is safe when used "as-is", but also because it provides a clear path to even higher levels of safety via a simple screening process.

Joshua LevyAll the views expressed here are those of Joshua Levy, and nothing here is official JDRF or JDCA news, views, policies or opinions.
Blog: http://cureresearch4type1diabetes.blogspot.com
Web: http://joshualevy.pbworks.com/DiabetesCureReadyForHumanTrials

Monday, September 13, 2010

Note: I forgot one study in the original (Sept-13) version of this blog entry, but this updated (Sept-15) version includes that study and updates the counts and percentages. I'm sorry for the oversight.

In the US, we are starting the "Walking Season" when JDRF asks us to walk to raise money for cure. So I'd like to do my part, by reminding you all how important JDRF is to the human trials of potential cures for type-1 diabetes, which I track.

Let me give you the punch line up front: 73% of the treatments currently in human trials have been funded by JDRF. (And the number is 85% for the later phase trials!) This is an amazing impact; one that any non-profit should be proud of.

One new complication (which I am very happy to have!) is that there are now more studies which combine two different drugs into one treatment. In general, I give funding credit, if the organization in the past funded any component of a combination treatment, or if they are funding the current combined treatment. Also, I list experiments separately if they use at least one different drug. For example, There are currently about six different trials going on for Diamyd's GAD65, both phase-III and phase-II, however all of these are covered by the one listing in the phase-III section. However, the clinical trial using Diamyd's GAD65 and lansoprazole and sitagliptin together gets it's own listing, in the phase-II section.

Last year, I didn't think there were enough trials aimed at established (non-honeymoon) diabetics, to mark them separately, but this year, I think there are. The trials marked E/NH below include patients who have had type-1 diabetes for more than one year, and so are out of the honeymoon period. Other treatments might end up helping established diabetics, but these are the ones being actively tested right now. I was surprised at how many there are. There is a general belief that all the current clinical trials are for honeymoon diabetics, or that JDRF's funding is somehow only going to curing honeymooners. It is true that none of the phase-III studies are aimed at established type-1 diabetes, but phase-II contains 37% non-honeymoon trials, and phase-I contains 50% (with JDRF funding 81% of the non-honeymoon trials).

Cures in Phase-III Human Trials
Summary: there are 4, and all of the treatments have been funded by JDRF.

Diamyd's GAD65

TolerRx's CD3

MacroGenics's CD3

Andromedia's DiaPep227

All of these treatments have more than one study active right now.

Cures in Phase-II Human Trials
Summary: there are 16, and 13 of them have been funded by JDRF, either directly or indirectly through ITN. Here are the treatments that have been funded by JDRF:

Abatacept by Orban at Joslin Diabetes Center

Diabecell by Living Cell Technologies (E/NH)

Diamyd's GAD65 and lansoprazole and sitagliptin

Exsulin (previously INGAP) by Exsulin (E/NH)

Kineret / Anakinra by Mandrup-Poulsen at Steno Diabetes Center

Liraglutide at Hvidovre University Hospital (E/NH)

PROCHYMAL by Osiris Therapeutics

Rituximab by Pescovitz at Indiana

Sitagliptin by Garg (E/NH)

Sitagliptin and Lansoprazole at Sanford Health

Thymoglobulin (also known as ATG) by Gitelman

Umbilical Cord Blood Infusion by Haller at University of Florida

Xoma 52 by Xoma Corp (E/NH)

Not funded by JDRF:

Atorvastatin (Lipitor) by Willi at Children's Hospital of Philadelphia

Brod at University of Texas-Health Science Center

NI-0401 by NovImmune

Cures in Phase-I Human Trials
Summary: there are 13, and 7 of the are funded by JDRF and 6 are not. Here is the list funded by JDRF:

ATG and GCSF by Haller at University of Florida (E/NH)

BHT 3021 by Bayhill Theraputics (E/NH)

CGSF by Haller at University of Florida

Trucco at Children’s Hospital of Pittsburgh (E/NH)

IBC-VS01 by Orban at Joslin Diabetes Center

Proleukin and Rapamune by Greenbaum at Benaroya Research Institute (E/NH)

Lisofylline by DiaKine

Not funded by JDRF:

ATG and autotransplant by Burt at University of Sao Paulo

BCG by Faustman at MGH

CGSF and autotransplant by Esmatjes at Hospital Clinic of Barcelona (E/NH)

Encapsulated Islets at University clinical Hospital Saint-Luc (E/NH)

Etanercept (ENBREL) by Quattrin at University at Buffalo School of Medicine

Pioglitazone by Wilson at Stony Brook

This summary does not include Artificial Pancreas research, which I discuss separately.
Nor does it include the last group of eight stem cell trials.

Summary of all Trials
33 in total
9 not funded by JDRF
So 73% of the human trials currently underway are funded (either directly or indirectly) by JDRF. Everyone who donates to JDRF should be proud of this huge impact; and everyone who works for JDRF or volunteers for it, should be doubly proud.

It is important to remember, however, that although there are four treatments in Phase-III trials, we are not close to a cure for established type-1 diabetes. None of the treatments in Phase-III trials resulted in cures during their Phase-II trials. They all extended or increased the honeymoon phase in some way.

We have a long way to go, and that is where JDRF comes in.

Compared to Last Year

In 2009 there were 4 treatments in Phase-III trials, in 2010 there are 4 (no growth).
In 2009 there were 10 treatments in Phase-II trials, in 2010 there are 16 (growth of 60%, but see the discussion below).
In 2009 there were 13 treatments in Phase-I trials, in 2010 there are 13 (no growth).

Obviously, there is not the same level of growth as there was last year. I'm not sure if that is because last year had unusually large growth, or if this year has unusually small growth, or if we are hitting "equilibrium" in our clinical trials of possible cures. I'll discuss that in more detail in a future post, as time permits.

Another issue, is that the growth in phase-II trials is partly due to my including several clinical trials of drugs which are used to treat type-2 diabetes and are being tested on type-1 diabetes. Some of these drugs have shown success at lowering insulin requirements for type-1 diabetics, but I'm not sure if they are possible paths to a cure. They may just be better treatments. My plan on these is to wait about 9 more months and make a decision at that time if they are possible cures or just possible treatments. If they are not cures, I'll remove them from my comparison. The studies in this group include:

Liraglutide at Hvidovre University Hospital

Sitagliptin by Garg (E/NH)

Sitagliptin and Lansoprazole at Sanford Health

Discussion

I give an organization credit for funding a cure if it funded that cure at any point in it's development cycle.

I use the term "US Gov" for all the different branches and organizations within the United States of America's federal govenment (so includes NIDDK, NIAID, NICHD, etc.)

The ITN (Immune Tolerance Network) has JDRF as a major funder, so I count ITN as indirect JDRF funding.

I have made no attempt to find out how much funding different organizations gave to different research. This would be next to impossible for long research programs, anyway.

Funding of research is not my primary interest, so I don't spend a lot of time tracking down details in this area. I might be wrong on details.

I don't work for the US Gov, JDRF, or any of the other organizations discussed here. I'm on the Research Information Committee of the San Francisco Bay Area chapter of the of JDRF and an adviser to JDCA. I also own stock in several of the companies discussed here.

This is an update and extension to blog postings that I've made for the last two years:
http://cureresearch4type1diabetes.blogspot.com/2009/09/jdrf-funding-research-for-cure.html
http://cureresearch4type1diabetes.blogspot.com/2008/10/jdrf-funding-of-cure-research-phases-ii.html

Please think of this posting as being my personal "thank you" note to all the JDRF staff, volunteers, and everyone who donates money to research a cure for type-1 diabetes: Thank You!

Joshua LevyAll the views expressed here are those of Joshua Levy, and nothing here is official JDRF or JDCA news, views, policies or opinions.
Blog: http://cureresearch4type1diabetes.blogspot.com
Web: http://joshualevy.pbworks.com/DiabetesCureReadyForHumanTrials

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This blog discusses cures and preventatives for type-1 diabetes that are either in human trials or just about to start. Treatments for diabetes are not generally discussed here, unless they can turn into a cure or a preventative. My definition of a cure is this:1. Blood sugar control without testing and with doctor's visits 4 times a year, or less. Any cure must result in an average lifespan close to normal.2. Does not require a lifetime of immunsuppressive drugs, so it is not trading one treatment for another. (but a couple of operations, or a short course of drugs is OK)Obviously, this is my personal definition of a cure; yours may differ.Because a cure for type-1 diabetes is likely to involve a combination of several different drugs or treatments, I try to follow research into anything which may be an important part of the cure.

My Non-Conflict of Interest Statement

I don't work for a company involved in medical research; I never have.

I don't get paid in any way by any company doing medical research; I never have. And that includes free samples, free travel, or free anything.

None of the hours that I have put into my blog, or the posts that I make to any web site, has ever been paid for, nor have I gotten anything free. (Except for some very nice and heart felt thank-you emails, and those are worth more than money.)

My daughter has type-1 diabetes and participates in clinical trials. I sometimes report on trials that she participates in.